Exposure to lead from the environment continues to be one of the greatest hazards to the well being of thousands of children in the United States. The recognition of the toxicity of this metal to the developing central nervous system (CNS) is demonstrated by recent evidence indicating a lack of a threshold of lead-induced effects on cognitive function. Despite a great deal of knowledge gained in the last two decades on the morphological, neurochemical, and behavioral effects of lead on the developing CNS, the mechanism(s) underlying the observed effects are poorly understood. The goal of the proposed studies is to understand at the molecular and whole animal level, mechanism(s) underlying the relationship between lead exposure in children and experimental animals during development and associated neurological and behavioral dysfunction. Our preliminary studies suggest that a mechanism of lead toxicity in the developing CNS may result from its interaction at the zinc regulatory site of the N- Methyl-D-Aspartate (NMDA) receptor-ion channel complex. A novel finding in these studies is that the effects of lead on NMDA receptor-ion channel function is more pronounced in neuronal tissue from immature rats relative to adults, and that the in vitro effects are demonstrable in vivo. The post-synaptic NMDA receptor and the release of glutamate from pre-synaptic elements, appear to be involved in early morphogenesis and cell differentiation in the developing CNS as well as in use-dependent plastic processes such as Long Term Potentiation (LTP), a synaptic phenomenon thought to underlie some types of learning and memory. An understanding of the impact of environmental toxins, such as lead, on pre-synaptic and post-synaptic glutamatergic transmission is of paramount importance. We believe that our approach to the proposed studies is unique in that it provides an integration of neurochemical, tissue culture, and behavioral protocols. Furthermore, we believe that it is equally important in trying to understand ways of ameliorating or preventing lead-induced CNS effects. In this regard, our proposed studies will assess whether increased levels of dietary calcium can influence the course of lead-induced neurotoxicity.